Considerable progress has been made over the last two decades in our understanding of the pathophysiology of obstructive sleep apnea. Most such data suggest that an anatomically small pharyngeal airway is a key element in this pathophysiology with pharyngeal dilator muscles compensating for the anatomic deficiency awake, but not asleep. However, no measure of upper airway anatomy [imaging, Pcrit (pharyngeal closing pressure)] can account for more than a fraction of the variability in apnea severity. Thus, other processes must be importantly influencing apnea pathogenesis. However, most such mechanisms have been minimally studied to date and their relative impact remains unclear. These would include individual variability in: (a) ventilatory control stability (loop gain), (b) the ability of pharyngeal dilator muscles to respond to chemical and mechanical stimuli during sleep, and (c) arousal threshold: Thus, there are likely to be a range of apnea phenotypes with each pathophysiologic process playing a greater or lesser role in a given individual. Our Specific Aims in this grant are as follows: First, we plan to define each of these important physiologic characteristics that contribute to apnea pathogenesis in a relatively large group of subjects ranging from normal controls to individuals with severe apnea. We hypothesize that five or six clusters of these phenotypic traits will emerge and explain most of the variability in apnea severity. Second, we will conduct two pilot studies to determine if a particular phenotype predicts responsiveness to certain forms of therapy (oxygen to reduce loop gain and a sedative to lower arousal threshold). Finally, we will begin testing methods by which these phenotypic traits can be more easily and less invasively defined. We believe these studies will importantly improve our understanding of apnea pathophysiology and will hopefully begin to allow individualization of therapy based on phenotypic characteristics. [unreadable] [unreadable] [unreadable]